Colonic polyps and colon cancer - Mucosal Immunology · • Colorectal Ca
Transcript of Colonic polyps and colon cancer - Mucosal Immunology · • Colorectal Ca
Colonic polyps and colon cancer
Andrew Macpherson Director of Gastroentology
University of Bern
Improtance of the problem of colon cancers - Epidemiology
• Lifetime risk 5% • Incidence/105/annum (US Detroit black
35, Canada 26.9, Geneva 25.2, India, Bombay 3.7)
• Familial risk (≥2 first or second degree relative) 20%
• Mendelian inheritance 4%
Colon polyps can develop into colon
cancer if left to grow for long
enough
Colonic polyps
Colonoscopy image Histology
Normal
Adenoma
Colon cancer
Colonoscopy image Histology
Two lines of evidence for the polypècarcinoma sequence
- Histopathology - Clinical observations on the
long term effects of removing polyps at colonoscopy
Evidence for the polyp carcinoma sequence –
Histopathology 1. Many carcinomas have adenomas at their edge St Marks Hospital series of 1961 carcinomas: 278
with contiguous adenoma (Morson, B. 1974 Proc. Royal Soc. Med. 67, 451)
2. Presence of histological malignant change within
polyps Presence of cancer/dysplasia within polyps especially
when >1cm diameter (see earlier slide)
Evidence for the polyp carcinoma sequence –
Clinical consequences of polyp removal
1. Removal of adenomas reduces later risk of cancer (Jarvinen et al 1995 Gastroenterology 108, 1405; Winawer et al., 1993 New England J. Med. 328, 901; Zauber et al., New England J. Med. 2012, 366, 687)
2. Patients with polyps >10mm not removed have increased risk of cancer (Stryker, S.J et al., 1987, Gastroenterology 93 1009).
Evidence for the polyp carcinoma sequence – Special case of familial adenomatous polyposis
This is an inherited condition, where there are 1000s of polyps in the colon
Ca colon always eventually develops unless the whole colon is removed surgically.
FAP colon after surgery
What are the mechanisms of colon cancer
development?
Intestinal epithelial cell renewal
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Epithelial cells continuously renew from stem cells Migrate upwards and are shed after 4-5 days
Genetic players in colon cancer
• Oncogenes • Oncosuppressor genes Stimulation of cell birth or inhibition of cell
death or cell cycle arrest • Stability genes Keep genetic alterations to a minimum
Two hit ‘Knudson’ hypothesis for oncosuppressor genes
Rare families have autosomal dominant familial adenomatous polyposis (FAP) where the colon is carpeted with polyps Most patients just have one or two polyps in the colon How can this be explained genetically? FAP colon
after surgery FAP colonoscopy
Two hit ‘Knudson’ hypothesis
Normalallele oncosuppressorgene
Two normal alleles
NO TUMOUR
Somatic mutantallele oncosuppressorgene
One normal allele
STILL NO TUMOUR
Somatic mutantalleles oncosuppressorgene
Two mutant alleles
ONCOSUPPRESSORDOES NOT WORK TUMOUR FORMATION
Somatic mutation 1
Somatic mutation 2
For a ‘sporadic’ tumour you need two successive mutations in one of the colonic stem cells - unlikely, but there are many stem cells
Two hit ‘Knudson’ hypothesis Normalallele oncosuppressorgene
One normal alleleNO TUMOUR
Inherited mutantallele oncosuppressorgene
Somatic mutantalleleoncosuppressorgene
One inherited + one somatic mutaion= 2 mutant allelesONCOSUPPRESSORDOES NOT WORK TUMOUR FORMATION
Somatic mutation
For a tumour with an inherited mutation, every cell in the body carries a mutant allele and you need ONE further mutation in a colonic stem cells - Likely that lots of tumours will form given so many stem cells
Gene for familial adenomatous polyposis
Over 800 different mutations for FAP
described with different clinical
phenotypes
Initially mapped to long arm of chromosome 5 through restriction fragment length polymorphism linkage Later cloned and sequenced: also called adenomatous polyposis coli (APC)
The FAP (APC) mutation works by initiating degradation of beta-catenin
– part of the WNT pathway
Another cause of multiple polyps (which can be confused with FAP clinically) is MAP
(MutYH adenomatous polyposis)
Polyposes through MTH1 or OGG1 mutations are described but rare
MAP requires two germline mutated alleles and is recessive
Other mutations accumulate in the carcinoma sequence
Vogelstein, B & Kinsler, K Trends in Genetics 9, 138
Hereditary non-polyposis colon
cancer = cancers which occur without a ‘carpet’ of polyps
WHEELER J M D et al. Gut 47:148-153
MutL related proteins
MutS related proteins
DNA error repair mechanisms
Lynch syndrome (hereditary non-polyposis colon cancer)
• R sided colon cancer associated with endometrial, bile duct, ovarian or pancreatic cancer
• 90% MSH2, MLH1, 7% MSH6, <5% PMS2 • 90% of those with known mutation will
develop colon cancer • Accelerated progression of polyps to cancer
Henry Lynch assembled large pedigrees of tumour patients
Henry Lynch NEJM 348,919
Modified Bethseda guidelines 2004
• Colorectal Ca <50 years • Synchronous, metachronous colorectal or
HNPCC tumours regardless of age • MSI-H histology in colon Ca <60 years • Colorectal Ca in one of more 1° relatives (one
Ca <50 years) • Colorectal Ca in two of more 1° or 2° relatives
regardless of age 80-90% sensitivity, 20% specificity for HNPCC
Microsatellite instability
• >30% markers unstable = MSI-H Bethesda +ve 50% sensitivity, unselected Ca colon
10% specificity for HNPCC • <30% markers unstable = MSI-L • 0 markers unstable = MSI negative
Testing
Immunohistochemistry
80% sensitivity, 85% specificity for HNPCC
Methylguanine methyl transferase
MLH1
Modifier genes in colon cancer
Heterogeneous colon cancer pathways
Serrated polyps: ‘sporadic MSI-H’
Serrated polyps: raf mutation
Adenomas: methyl guanine methyltransferase methylation, ras mutation
Lynch syndrome
FAP, MUTYH or sporadic Vogelstein-Knudson polyp cancer pathway
Screening criteria AGA
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Alternatives for screening asymptomatic patients with ‘normal’ CRC risk
Test Utility ‘Recommendations’ Blood test (e.g. Sept9) Avoids stool based tests and
invasive procedures Sensitivity for polyps and early cancers is very low (20-50%)
Limited role in current screening protocols, the place of the test remains to be defined.
High-Sensitivity Fecal Occult Blood Test (FOBT) or Stool Test; or Fecal Immunochemical Test (FIT)
Need to obtain 3 successive stool specimens and take special diet and altered drug regime for 1 week beforehand Sensitivity 70-80% specificity 85-95%
Every year, with colonoscopy when positive (large studies show a consistent CRC mortality reduction of 15-40%).
Flexible sigmoidoscopy Effective for only lower third of colon: outside Switzerland nurses allowed to do the examination.
Every five years recommended ± FOB every 3 years (mortality reduction up to 50%).
Colonoscopy or CT colonography
(Almost) complete examination invasive potential complications. Miss rate for polyps 5-10%
Every 10 years (mortality reduction 20-90% depending on protocol used).
Genetic polyp syndromes
Test Gene Risk of malignant tumour Familial adenomatous polyposis
APC #5 (also Gardner’s: osteomas and desmoids, Turcot’s: medulloblastoma, and attenuated FAP 5’, 3’ and I1307K, E1317Q mutations
CRC near 100% Duodenal 5-12% Pancreatic and thyroid 2%
Peutz-Jeghers syndrome (hamartomatous polyps of GI tract with smooth muscle in lamina propria, mucocutaneous pigmentation)
STK11 serine/threonine kinase on #19
All GI 2-13%, small intestine RR=13, pancreatic RR=100, breast and uterine RR=8
Juvenile polyposis (juvenile polyps: hamartomas with adenomas)
MADH4 CRC <50%
Cowden syndrome (multiple hamatomas, stomach, small intestine and colon)
PTEN CRC minimal, thyroid, breast and uterine increase
When genetics are unknown an alternative is to screen patients with
colonoscopy
Summary
• Genetic colon cancer relatively common
• Underappreciated and underinvestigated in our system
• Probably largely avoidable tumours